RESUMO
Anoikis, a form of apoptosis resulting from the loss of cell-extracellular matrix interaction, is a significant barrier to cancer cell metastasis. However, the epigenetic regulation of this process remains to be explored. Here, we demonstrate that the histone deacetylase sirtuin 6 (SIRT6) plays a pivotal role in conferring anoikis resistance to colorectal cancer (CRC) cells. The protein level of SIRT6 is negatively correlated with anoikis in CRC cells. The overexpression of SIRT6 decreases while the knockdown of SIRT6 increases detachment-induced anoikis. Mechanistically, SIRT6 inhibits the transcription of N-myc downstream-regulated gene 1 (NDRG1), a negative regulator of the AKT signaling pathway. We observed the up-regulation of SIRT6 in advanced-stage CRC samples. Together, our findings unveil a novel epigenetic program regulating the anoikis of CRC cells.
Assuntos
Anoikis , Proteínas de Ciclo Celular , Neoplasias Colorretais , Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular , Sirtuínas , Humanos , Anoikis/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Sirtuínas/metabolismo , Sirtuínas/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Regulação para Baixo , Transdução de Sinais , Epigênese GenéticaRESUMO
Friction interfaces in liquid-embedded composite lubrication coatings commonly comprise a combination of discontinuous fluid films and rough solid contact surfaces, which together ensure easy shearing and a prolonged wear life. However, achieving high efficacy in mixed lubrication poses a challenge due to the conflicting nature of enhanced migration freedom for the liquid lubricant and increased mechanical strength of the solid matrix. Recent efforts have focused on incorporating reinforcing fillers to develop multicomponent, multiphase composites that can address this paradox. Here, we describe a modified attapulgite (APT) with strong biphasic wettability via the oil decompressive osmosis treatment on APT nanocontainers grafted with long nonpolar alkyl chains. This modified APT enables control over the size, distribution, and mobility of lubricant droplets by constructing a Pickering emulsion and toughens the solid-phase matrix through dispersion strengthening. Additionally, the introduction of APT induces the formation of a solid tribofilm during friction, which possesses a higher oil adsorption capacity, as verified through first-principles calculations based on density functional theory (DFT). Consequently, the fluid films can be replenished by the fracture of nanocontainers and adsorption from the bulk phase; further comprehensive and effective regulation of the friction interface leads to low friction and wear.
RESUMO
The present study investigated whether physical cleansing can reduce the mindset effect in problem-solving in two experiments. Both experiments followed the same procedure. In the first stage, participants formed a mindset through the Luchins' water-jar task (Experiment 1) or the idiom maze task (Experiment 2). The second stage is cleansing manipulation. In Experiment 1, participants were asked to clean their hands with wipes (cleansing condition) or examine the packaging of the wipes (no-cleansing condition). In Experiment 2, participants were asked to watch a washing-hands video (cleansing condition) or watch an examining-pen video (no-cleansing condition). At last, all participants completed the mindset effect test problems. The results showed that the participants in the cleansing condition were less affected by the mindset than those in the no-cleansing condition, indicating that physical cleansing reduced the mindset effect. Our results provide new evidence for the clean-slate effects and support the hypothesis that physical cleansing is an embodied process of psychological separation.
Assuntos
Higiene , Resolução de Problemas , HumanosRESUMO
Patients who have undergone surgery in early life may be at elevated risk for suffering neuropathic pain in later life. The risk factors for this susceptibility are not fully understood. Here, we used a mouse chronic pain model to test the hypothesis that early exposure to the general anesthetic (GA) Isoflurane causes cellular and molecular alterations in dorsal spinal cord (DSC) and dorsal root ganglion (DRG) that produces a predisposition to neuropathic pain via an upregulation of the mammalian target of the rapamycin (mTOR) signaling pathway. Mice were exposed to isoflurane at postnatal day 7 (P7) and underwent spared nerve injury at P28 which causes chronic pain. Selected groups were treated with rapamycin, an mTOR inhibitor, for eight weeks. Behavioral tests showed that early isoflurane exposure enhanced susceptibility to chronic pain, and rapamycin treatment improved outcomes. Immunohistochemistry, Western blotting, and q-PCR indicated that isoflurane upregulated mTOR expression and neural activity in DSC and DRG. Accompanying upregulation of mTOR and rapamycin-reversible changes in chronic pain-associated markers, including N-cadherin, cAMP response element-binding protein (CREB), purinergic P2Y12 receptor, glial fibrillary acidic protein (GFAP) in DSC; and connexin 43, phospho-extracellular signal-regulated kinase (p-ERK), GFAP, Iba1 in DRG, were observed. We concluded that early GA exposure, at least with isoflurane, alters the development of pain circuits such that mice are subsequently more vulnerable to chronic neuropathic pain states.
Assuntos
Anestésicos Gerais , Dor Crônica , Isoflurano , Neuralgia , Animais , Camundongos , Dor Crônica/tratamento farmacológico , Modelos Animais de Doenças , Isoflurano/efeitos adversos , Mamíferos , Neuralgia/tratamento farmacológico , Transdução de SinaisRESUMO
AIFM2 is a crucial NADH oxidase involved in the regulation of cytosolic NAD+. However, the role of AIFM2 in the progression of human cancers remains largely unexplored. Here, we elucidated the clinical implications, biological functions, and molecular mechanisms of AIFM2 in hepatocellular carcinoma (HCC). We found that AIFM2 is significantly upregulated in HCC, which is most probably caused by DNA hypomethylation and downregulation of miR-150-5p. High expression of AIFM2 is markedly associated with poor survival in patients with HCC. Knockdown of AIFM2 significantly impaired, while forced expression of AIFM2 enhanced the metastasis of HCC both in vitro and in vivo. Mechanistically, increased mitochondrial biogenesis and oxidative phosphorylation by activation of SIRT1/PGC-1α signaling contributed to the promotion of metastasis by AIFM2 in HCC. In conclusion, AIFM2 upregulation plays a crucial role in the promotion of HCC metastasis by activating SIRT1/PGC-1α signaling, which strongly suggests that AIFM2 could be targeted for the treatment of HCC.
RESUMO
Some patients with chronic refractory cough have high levels of pulmonary IFN-γ and IFN-γ-producing T lymphocytes. Pulmonary IFN-γ administration causes acute airway lymphocytic inflammation and cough hypersensitivity by increasing the number of pulmonary IFN-γ-producing T lymphocytes, but these lymphocytes may be recruited from other organs. Intraperitoneal IFN-γ injection can increase the spleen weight of mice. It remains elusive whether pulmonary IFN-γ can induce chronic airway lymphocytic inflammation and cough hypersensitivity by stimulating the proliferation of IFN-γ -producing T lymphocytes in the spleen. Here, we found that pulmonary IFN-γ administration induced chronic airway inflammation and chronic cough hypersensitivity with an increased number of IFN-γ-producing T lymphocytes in the spleen, blood and lung. Pulmonary IFN-γ administration also increased 1) the proliferation of spleen lymphocytes in vivo and 2) the IP-10 level and CXCR3+ T lymphocyte numbers in the spleen and lung of mice. IP-10 could promote the proliferation of spleen lymphocytes in vitro but not blood lymphocytes or lung-resident lymphocytes. AMG487, a potent inhibitor of binding between IP-10 and CXCR3, could block pulmonary IFN-γ instillation-induced chronic airway lymphocytic inflammation and the proliferation of IFN-γ-producing T lymphocytes in mouse spleens. In conclusion, intrapulmonary IFN-γ instillation may induce the proliferation of splenic IFN-γ-producing T lymphocytes through IP-10 and the CXCR3 pathway. The IFN-γ-producing T lymphocytes in blood, partly released from the mouse spleen, may be partly attracted to the lung by pulmonary IP-10 through the CXCR3 pathway. IFN-γ-producing T lymphocytes and IFN-γ in the lung may cause chronic airway lymphocytic inflammation and chronic cough hypersensitivity.
Assuntos
Quimiocina CXCL10 , Baço , Camundongos , Animais , Baço/metabolismo , Tosse , Quimiocina CXCL9 , Pulmão/metabolismo , Interferon gama/metabolismo , Inflamação , Receptores CXCR3RESUMO
T lymphopenia, occurring in the early phase of sepsis in response to systemic inflammation, is commonly associated with morbidity and mortality of septic infections. We have previously shown that a sufficient number of T cells is required to constrain Toll-like receptors (TLRs) mediated hyperinflammation. However, the underlying mechanisms remains unsolved. Herein, we unveil that CD4+ T cells engage with MHC II of macrophages to downregulate TLR pro-inflammatory signaling. We show further that the direct contact between CD4 molecule of CD4+ T cells or the ectodomain of CD4 (soluble CD4, sCD4), and MHC II of resident macrophages is necessary and sufficient to prevent TLR4 overactivation in LPS and cecal ligation puncture (CLP) sepsis. sCD4 serum concentrations increase after the onset of LPS sepsis, suggesting its compensatory inhibitive effects on hyperinflammation. sCD4 engagement enables the cytoplasmic domain of MHC II to recruit and activate STING and SHP2, which inhibits IRAK1/Erk and TRAF6/NF-κB activation required for TLR4 inflammation. Furthermore, sCD4 subverts pro-inflammatory plasma membrane anchorage of TLR4 by disruption of MHC II-TLR4 raft domains that promotes MHC II endocytosis. Finally, sCD4/MHCII reversal signaling specifically interferes with TLR4 but not TNFR hyperinflammation, and independent of the inhibitive signaling of CD40 ligand of CD4+ cells on macrophages. Therefore, a sufficient amount of soluble CD4 protein can prevent excessive inflammatory activation of macrophages via alternation of MHC II-TLR signaling complex, that might benefit for a new paradigm of preventive treatment of sepsis.
Assuntos
Antígenos CD4 , Sepse , Humanos , Antígenos CD4/metabolismo , Receptor 4 Toll-Like/genética , Lipopolissacarídeos/metabolismo , Macrófagos/metabolismo , Sepse/genética , Sepse/metabolismo , Inflamação/metabolismoRESUMO
Empathy involves both empathic ability and empathic motivation. An important topic has been how to measure empathic ability and motivation simultaneously in both clinical and non-clinical samples and across different cultures. The Empathy Components Questionnaire (ECQ) is a self-report questionnaire that measures empathic ability and motivation in a questionnaire. The current study aimed to validate the Mandarin Chinese version of the ECQ (ECQ-Chinese) in three Chinese samples. In study 1, a total of 538 Chinese participants (Sample 1) completed the ECQ-Chinese via an online survey, and existing measures of empathy and related constructs which were used for criterion validity. In study 2, a total of 104 participants (Sample 2) were recruited again from sample 1 and completed the ECQ-Chinese three weeks later to investigate test-retest reliability. In study 3, a further 324 participants (Sample 3) completed the ECQ-Chinese for confirmatory factor analysis. The results showed that the ECQ-Chinese has a good internal consistency reliability, split-half reliability, and criterion validity (Study 1), and a good test-retest reliability (Study 2). Further, Study 3 found that a 22-item ECQ-Chinese consisting of five subscales had a good construct validity, convergence validity and discriminate validity, demonstrating it to be a suitable tool for the measurement of empathic ability and motivation in Chinese samples and to carry out cross-cultural studies of empathy and its components.
Assuntos
Empatia , Humanos , Reprodutibilidade dos Testes , Psicometria/métodos , Inquéritos e Questionários , Autorrelato , ChinaRESUMO
PURPOSE: Respiratory viral infection increases the number of lung-resident T lymphocytes, which enhance cough sensitivity by producing interferon-γ (IFN-γ). It is poorly understood why IFN-γ-secreting T lymphocytes persist for a long time when the respiratory viruses have been removed. METHODS: Repeated pulmonary administration of IFN-γ and intraperitoneal injection with different inhibitors were used to study the effects of pulmonary IFN-γ in mice and guinea pigs. RESULTS: IFN-γ administration caused the increasing of IFN-γ-secreting T lymphocytes in both lung and blood, followed by the elevated physiological level of IFN-γ in the lung, the airway inflammation and the airway epithelial damage. IFN-γ administration also enhanced the cough sensitivity of guinea pigs. IFN-γ activated the STAT1 and extracellular signal-regulated kinase (ERK) pathways in lung tissues, released IFN-γ-inducible protein 10 (IP-10), and resulted in F-actin accumulation in lung-resident lymphocytes. The CXC chemokine receptor 3 (CXCR3) inhibitor potently suppressed all the IFN-γ-induced inflammatory changes. The STAT1 inhibitor mitigated IFN-γ-secreting T lymphocytes infiltration by inhibiting T lymphocytes proliferation. F-actin accumulation and the ERK1/2 pathway contributed to pulmonary IFN-γ-induced augmentation of the airway inflammation and increasing of IFN-γ-secreting T lymphocytes in blood. CONCLUSIONS: High physiological levels of IFN-γ in the lung may cause pulmonary lymphocytic inflammation and cough hypersensitivity by increasing the number of IFN-γ-secreting T lymphocytes through the IP-10 and CXCR3 pathways.
RESUMO
Background: In this study, we enrolled 862 patients with Crohn's disease (CD) in China to investigate the correlation between serum vitamin D (SVD) and serum lipids, inflammatory biomarkers, and important clinical parameters. Materials and Methods: 25(OH)D was measured by LS/MS/MS. Correlation analysis, chi-square tests, and logistic regression analysis were performed to determine the correlations between vitamin D and potential risk factors when vitamin D levels were lower than 10 ng/mL or 20 ng/mL. Results: The incidence of severe vitamin D deficiency (SVD < 10 ng/mL) in patients with CD was significantly higher than that in healthy controls (28.9 vs. 9.5%). Multinomial logistic regression analysis showed that penetrating disease [odds ratio (OR) = 2.18], low levels of high-density lipoprotein cholesterol (HDL) (OR = 1.91), high erythrocyte sedimentation rate (OR = 1.73), and platelet count (PLT) (OR = 2.71) were regarded as predictors of severe vitamin D deficiency, while only PLT (OR = 1.90) and HDL (OR = 1.76) were considered as predictors of mild vitamin D deficiency (SVD 10-20 ng/mL). Conclusion: Our results confirm a higher incidence of severe vitamin D deficiency in patients with CD in China and show that vitamin D deficiency could result from the combined effects of penetrating disease, inflammation, and low levels of HDL.
RESUMO
This paper proposes a sustainable management and decision-making model for COVID-19 control in schools, which makes improvements to current policies and strategies. It is not a case study of any specific school or country. The term one-size-fits-all has two meanings: being blind to the pandemic, and conducting inflexible and harsh policies. The former strategy leads to more casualties and does potential harm to children. Conversely, under long-lasting strict policies, people feel exhausted. Therefore, some administrators pretend that they are working hard for COVID-19 control, and people pretend to follow pandemic control rules. The proposed model helps to alleviate these problems and improve management efficiency. A customized queue model is introduced to control social gatherings. An indoor-outdoor tracking system is established. Based on tracing data, we can assess people's infection risk, and allocate medical resources more effectively in case of emergency. We consider both social and technical feasibility. Test results demonstrate the improvements and effectiveness of the model. In conclusion, the model has patched up certain one-size-fits-all strategies to balance pandemic control and normal life.
Assuntos
COVID-19 , COVID-19/epidemiologia , Criança , Humanos , Política Organizacional , Pandemias/prevenção & controle , Políticas , Instituições AcadêmicasRESUMO
Evidence has suggested the potential of tumor-educated platelets as a biomarker trove for cancer diagnostics, but the difficulty in isolation limits its application. Since most of the circulating RNAs are derived from platelets, the change of RNA profile in platelets may lead to altered RNA expression in serum. Here, we identified a panel of platelet-associated long non-coding RNAs (lncRNAs) and evaluated its diagnostic capacity in serum of colorectal cancer (CRC) patients. Four lncRNAs, LNCAROD, SNHG20, LINC00534, and TSPOAP-AS1, were upregulated in both platelets and serum of CRC patients. A binary logistic model derived from them has validated area under roc curve of 0.78 indicating great performance. Furthermore, the expression levels of LNCAROD and TSPOAP-AS1 were correlated with cancer staging and tumor location. Together, our results add novel lncRNA biomarkers to the list of blood tests for CRC diagnostics and provide molecular evidence for the cross-talk between CRC platelets and serum.
Assuntos
Ácidos Nucleicos Livres , Neoplasias Colorretais , RNA Longo não Codificante , Biomarcadores , Biomarcadores Tumorais/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , RNA Longo não Codificante/genética , Curva ROCRESUMO
N6-methyladenosine (m6A), the most prevalent internal modification in eukaryotic mRNAs, regulates gene expression at the post-transcriptional level. The reader proteins of m6A, mainly YTH domain-containing proteins, specifically recognize m6A-modified mRNAs and regulate their metabolism. Recent studies have highlighted essential roles of m6A readers in the initiation and development of human cancers. In this review, we summarize recent findings about the biological functions of YTH domain proteins in cancers, the underlying mechanisms, and clinical implications. Gene expression reprogramming by dysregulated m6A reader proteins offers potential targets for cancer treatment, while targeted m6A editors and readers provide tools to manipulate m6A metabolism in cancers.
Assuntos
Adenosina/análogos & derivados , Neoplasias/genética , Domínios Proteicos/genética , RNA Mensageiro/genética , Adenosina/genética , Animais , Expressão Gênica/genética , Humanos , Metilação , Processamento Pós-Transcricional do RNA/genéticaRESUMO
Aim: To investigate the value of galectin-3 in the diagnosis of acute coronary syndrome (ACS) and the assessment of coronary artery lesions. Methodology: This study recruited 157 patients with coronary artery disease where 102 and 55 of them were subsequently grouped as ACS and non-ACS, respectively. The severity of coronary artery lesions was evaluated by Gensini score and the number of vessels involved. Results: Receiver operator characteristics analyses of galectin-3 yielded an area under the curve of 0.679 in diagnosing ACS. The galectin-3 levels were correlated with Gensini score and the number of vessels involved. Conclusion: Our study demonstrated that galectin-3 is an effective auxiliary biomarker for the diagnosis of ACS and assessment of coronary artery lesions.
Assuntos
Síndrome Coronariana Aguda/diagnóstico , Biomarcadores/metabolismo , Proteínas Sanguíneas/metabolismo , Doença da Artéria Coronariana/patologia , Vasos Coronários/patologia , Galectinas/metabolismo , Índice de Gravidade de Doença , Síndrome Coronariana Aguda/metabolismo , Estudos de Casos e Controles , Angiografia Coronária , Doença da Artéria Coronariana/metabolismo , Vasos Coronários/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: To assess and limit the SARS-CoV-2 exposure risk from symptomless individuals in the hospital setting, molecular and serological screening of staff and patients attending a tertiary hospital in China was conducted. METHODS: SARS-CoV-2 RNA was tested by quantitative RT-PCR. Anti-SARS-CoV-2 IgM and IgG were screened initially with two lateral flow immunoassays (LFIs) and further confirmed with three chemiluminescence immunoassays (CLIAs). The assay performance was assessed using archived samples from 32 confirmed COVID-19 cases and 80 healthy individuals. RESULTS: Between April 24 and May 8, 2020, 16,043 subjects (7,392 medical staff, 4,714 inpatients, 1,209 chaperones, 1,705 outpatients, and 1,023 fever clinic patients) were screened. No subject tested positive for viral RNA. Seventy-three (0.46%) tested positive for IgM or IgG on the initial LFI screening, of whom 63 were investigated with CLIAs: 2 (0.01%) were confirmed as seroreactive and 18 (0.11%) were indeterminate. Unconfirmed seroreactivity was significantly more frequent in fever clinic patients. The CLIAs showed similar (95.0-100%) IgM or IgG specificity but higher IgG sensitivity (93.75-96.88% vs. 31.25-81.25%) than the LFIs. The confirmed seropositive cases included a previously discharged COVID-19 patient and an undiagnosed symptomless patient showing detectable IgM and IgG over 35 days of follow-up. No transmission was evidenced within the corresponding family cluster. CONCLUSIONS: Low SARS-CoV-2 prevalence and limited exposure risk were observed. Seroprevalence varied between 0.012% and 0.12% according to the testing algorithm and the confirmation criteria used, indicating that quality standards for serological tests are needed. Protective immunity in asymptomatic COVID-19 patients who recovered needs to be investigated further, but the associated risk of transmission appeared limited.
RESUMO
NOXA, a BH3-only proapoptotic protein involved in regulating cell death decisions, is highly expressed but short-lived in colorectal cancer (CRC). Neddylated cullin-5 (CUL5)-mediated ubiquitination and degradation of NOXA is crucial to prevent its overaccumulation and maintain an appropriate action time. However, how this process is manipulated by CRC cells commonly exposed to oxidative stress remain unknown. The peroxiredoxin PRDX1, a conceivable antioxidant overexpressed in CRC tissues, has been shown to inhibit apoptosis and TRAF6 ubiquitin-ligase activity. In this study, we found that PRDX1 inhibits CRC cell apoptosis by downregulating NOXA. Mechanistically, PRDX1 promotes NOXA ubiquitination and degradation, which completely depend on CUL5 neddylation. Further studies have demonstrated that PRDX1 oligomers bind with both the Nedd8-conjugating enzyme UBE2F and CUL5 and that this tricomplex is critical for CUL5 neddylation, since silencing PRDX1 or inhibiting PRDX1 oligomerization greatly dampens CUL5 neddylation and NOXA degradation. An increase in reactive oxygen species (ROS) is not only a hallmark of cancer cells but also the leading driving force for PRDX1 oligomerization. As shown in our study, although ROS play a role in upregulating NOXA mRNA transcription, ROS scavenging in CRC cells by N-acetyl-L-cysteine (NAC) can significantly reduce CUL5 neddylation and extend the NOXA protein half-life. Therefore, in CRC, PRDX1 plays a key role in maintaining intracellular homeostasis under conditions of high metabolic activity by reinforcing UBE2F-CUL5-mediated degradation of NOXA, which is also evidenced in the resistance of CRC cells to etoposide treatment. Based on these findings, targeting PRDX1 could be an effective strategy to overcome the resistance of CRC to DNA damage-inducing chemotherapeutics.
Assuntos
Neoplasias Colorretais/enzimologia , Proteínas Culina/metabolismo , Peroxirredoxinas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Apoptose , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Proteínas Culina/genética , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HEK293 , Células HT29 , Meia-Vida , Humanos , Peroxirredoxinas/genética , Multimerização Proteica , Proteólise , Proteínas Proto-Oncogênicas c-bcl-2/genética , Espécies Reativas de Oxigênio/metabolismo , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/metabolismo , UbiquitinaçãoRESUMO
The deacetylase SIRT1 has been reported to play a critical role in regulating neurogenesis, which may be an adaptive processes contributing to recovery after stroke. Our previous work showed that the antioxidant capacity of Momordica charantia polysaccharides (MCPs) could protect against cerebral ischemia/reperfusion (I/R) after stroke. However, whether the protective effect of MCPs on I/R injury is related to neural stem cell (NSC) proliferation remains unclear. In the present study, we designed invivo and invitro experiments to elucidate the underlying mechanisms by which MCPs promote endogenous NSC proliferation during cerebral I/R. Invivo results showed that MCPs rescued the memory and learning abilities of rats after I/R damage and enhanced NSC proliferation in the rat subventricular zone (SVZ) and subgrannular zone (SGZ) during I/R. Invitro experiments demonstrated that MCPs could stimulate the proliferation of C17.2 cells under oxygen-glucose deprivation (OGD) conditions. Further studies revealed that the proliferation-promoting mechanism of MCPs relied on increasing the activity of SIRT1, decreasing the level of acetylation of ß-catenin in the cytoplasm, and then triggering the translocation of ß-catenin into the nucleus. These data provide experimental evidence that the up-regulation of SIRT1 activity by MCPs led to an increased cytoplasmic deacetylation of ß-catenin, which promoted translocation of ß-catenin to the nucleus to participate in the signaling pathway involved in NSC proliferation. The present study reveals that MCPs function as a therapeutic drug to promote stroke recovery by increasing the activity of SIRT1, decreasing the level of acetylated ß-catenin, promoting the nuclear translocation of ß-catenin and thereby increasing endogenous NSC proliferation.
Assuntos
Proliferação de Células/efeitos dos fármacos , Momordica charantia , Células-Tronco Neurais/efeitos dos fármacos , Extratos Vegetais/farmacologia , Polissacarídeos/farmacologia , Traumatismo por Reperfusão/metabolismo , Sirtuína 1/metabolismo , Animais , Células-Tronco Neurais/metabolismo , Neurogênese/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacosRESUMO
Interleaved practice (i.e., exemplars from different categories are intermixed within blocks) has been shown to enhance induction performance compared to blocked practice (i.e., exemplars from the same category are presented sequentially). The main aim of the present study was to examine explanations of why interleaved practice produces this benefit in category induction (known as the interleaving effect). We also evaluated two hypotheses, the attention attenuation hypothesis and the discriminative-contrast hypothesis, by collecting data on participants' fixation on exemplars, provided by eye-tracking data, and manipulating the degree of discriminative-contrast. In Experiments 1 and 2, participants were instructed to learn the style of 12 new artists in blocked and interleaved practice in fixed-paced and self-paced learning conditions, respectively. We examined fixation durations for six positions (temporal sequence of exemplars presented in each block) using eye-tracking. The results of the two experiments, based on eye-tracking data, suggested that attention attenuation may not be the primary mechanism underlying the interleaving effect in category induction. In Experiment 3, we manipulated the degree of discriminative-contrast to examine the impact on the interleaving effect in category induction. The results showed that the main effect of the degree of discriminative-contrast was significant, and performance in the high-contrast condition was significantly better than those in the medium-contrast and low-contrast conditions. Thus, the current results support the discriminative-contrast hypothesis rather than the attention attenuation hypothesis.
RESUMO
Traumatic brain injury (TBI) is a leading cause of morbidity and mortality among military service members and civilians in the United States. Despite significant advances in the understanding of TBI pathophysiology, several clinical reports indicate that multiple genetic and epigenetic factors can influence outcome. Homocysteine (HCY) is a non-proteinogenic amino acid, the catabolism of which can be dysregulated by stress, lifestyle, aging, or genetic abnormalities leading to hyperhomocysteinemia (HHCY). HHCY is a neurotoxic condition and a risk factor for multiple neurological and cardiovascular disorders that occurs when HCY levels is clinically > 15 µM. Although the deleterious impact of HHCY has been studied in human and animal models of neurological disorders such as stroke, Alzheimer's disease and Parkinson's disease, it has not been addressed in TBI models. This study tested the hypothesis that HHCY has detrimental effects on TBI pathophysiology. Moderate HHCY was induced in adult male Sprague Dawley rats via daily administration of methionine followed by impact-induced traumatic brain injury. In this model, HHCY increased oxidative stress, upregulated expression of proteins that promote blood coagulation, exacerbated TBI-associated blood-brain barrier dysfunction and promoted the infiltration of inflammatory cells into the cortex. We also observed an increase of brain injury-induced lesion size and aggravated anxiety-like behavior. These findings show that moderate HHCY exacerbates TBI outcomes and suggest that HCY catabolic dysregulation may be a significant biological variable that could contribute to TBI pathophysiology heterogeneity.